Stem cells can self-renew or differentiate into multiple cell types. These properties promise great therapeutic potentials in regenerative medicine. Understanding the molecular mechanisms regulating stem cell identity and maintenance will provide fundamental knowledge about human health and likely accelerate the use of stem cells in regenerative medicine. Epigenetic mechanisms regulate dynamic changes of gene expression profiles to influence stem cell self-renewal and differentiation. I am especially interested in investigating Polycomb Group (PcG)-mediated epigenetic regulation of stem cells. My previous work characterized a novel mechanism regulating a PcG complex, a key epigenetic modifier, during the transition from pluripotency to developmentally restricted cell fates. Currently, I am investigating PcG functions and their interaction with Piwi in Drosophila ovarian germline, which is tractable to genetic, genomic, molecular, as well as cell biological analyses. Piwi is a master regulator of germline stem cells. During the mentored phase, I will characterize Piwi-PcG interaction and determine how this interaction impacts Drosophila ovarian germline and germline stem cells. During the independent phase, I will characterize the molecular effects of PcG functions and Piwi-PcG interaction in Drosophila germline. This study will have significant impact on stem cell biology, epigenetics, as well as regenerative medicine. Candidate: My long-term research goal is to investigate how epigenetic mechanisms impact human health and disease, specifically to understand how epigenetic mechanisms regulate complex tissues. My long-term career goals are to maintain a successful independent research program and educate future scientists. The K99/R00 Pathway to Independence Award will allow me to gain the critical training needed to achieve my long-term research and career goals. I will use experimental data obtained from this proposal as the basis for my own independent research. Training environment: Dr. Haifan Lin (mentor), my advisory committee, and Yale University provide an excellent training program, an intellectually stimulating community, and a well-supported research environment. In this training environment I will gain scientific knowledge, research expertise, grant writing ability, lab management skill, and additional leadership skills. All these will enhance my ability to obtain a tenure-track faculty position and achieve my long-term research and career goals. PUBLIC HEALTH RELEVANCE: The self-renewal and differentiability of stem cells promise great therapeutic potentials in regenerative medicine. This proposal aims to understand the mechanisms regulating gene expression that program stem cell identity by using Drosophila as the model system. This work would reveal fundamental knowledge about stem cell biology, thereby accelerating the use of stem cells in regenerative medicine.